Inorganically surface-modified polymers and methods for making and using them

ABSTRACT

In alternative embodiments, the invention provides articles of manufacture comprising biocompatible nanostructures comprising PolyEther EtherKetone (PEEK) surface-modified (surface-nanopatterned) to exhibit nanostructured surfaces that promote osseointegration and bone-bonding for, e.g., joint (e.g., knee, hip and shoulder) replacements, bone or tooth reconstruction and/or implants, including their use in making and using artificial tissues and organs, and related, diagnostic, screening, research and development and therapeutic uses, e.g., as primary or ancillary drug delivery devices. In alternative embodiments, the invention provides biocompatible nanostructures that promote osseointegration and bone-bonding for enhanced cell and bone growth and e.g., for in vitro and in vivo testing, restorative and reconstruction procedures, implants and therapeutics.

CROSS REFERENCE TO RELATED APPLICATIONS

This U.S. utility patent application is a continuation under 35 U.S.C.§120 of U.S. patent application Ser. No. 14/685,487, filed Apr. 13,2015, which claims benefits under 35 U.S.C. §120 of U.S. patentapplication Ser. No. 13/176,907, filed Jul. 6, 2011, issued as U.S. Pat.No. 9,005,648, Apr. 14, 2015, which claims benefit of priority under 35U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. (USSN)61/361,815, filed Jul. 6, 2010. The contents of these applications areexpressly incorporated herein by reference in their entirely for allpurposes.

FIELD OF THE INVENTION

In alternative embodiments, the invention provides articles ofmanufacture comprising biocompatible nanostructures comprising PolyEtherEtherKetone (PEEK) or ultra-high-molecular-weight polyethylene (UHMWPE)surface-modified (surface-nanopatterned) to exhibit nanostructuredsurfaces that promote osseointegration and bone-bonding for, e.g., joint(e.g., knee, hip and shoulder) replacements, bone or toothreconstruction and/or implants, including their use in making and usingartificial tissues and organs, and related, diagnostic, screening,research and development and therapeutic uses, e.g., as primary orancillary drug delivery devices. In alternative embodiments, theinvention provides biocompatible nanostructures that promoteosseointegration and bone-bonding for enhanced cell and bone growth ande.g., for in vitro and in vivo testing, restorative and reconstructionprocedures, implants and therapeutics.

BACKGROUND OF THE INVENTION

PolyEther EtherKetone (PEEK) is increasingly being used in spinalimplants and investigated as a biomaterial for orthopedic implantsbecause of its mechanical toughness, resistance to thermal and chemicaldegradation and non-toxicity. Its main advantages over titanium are itsx-ray translucence and elastic modulus similar to that of bone. PEEK canbe easily viewed with radiography and magnetic resonance to assessimplant positioning and stability. It reduces stress shielding in boneand bone resorption, which are common problems from implanted metalswith mismatched elasticity properties. PEEK is only now beginning to beexplored as a material for joint replacements. It has been shown as anexcellent material for articulation in the joint; however, it does notinterface well with bone. There is a need for chemically ormicro/nanostructurally modified PEEK surfaces which adhere strongly tothe PEEK substrate and bond well with bone

SUMMARY

In alternative embodiments the invention provides products ofmanufacture comprising a thermoplastic polymer or a thermoplasticpolymer, or a PolyEther EtherKetone (PEEK), a PolyEtherKetoneKetone(PEKK), a PolyEther EtherKetone (PEEK), an ultra-high-molecular-weightpolyethylene (UHMWPE), a thermoplastic polymer as set forth in Table 1,a combination thereof or an equivalent material thereof (e.g., see Table1, below), and having a biocompatible surface,

wherein optionally the product of manufacture substantially comprises orconsists essentially of (excepting its biocompatible surface) athermoplastic polymer, or a PolyEther EtherKetone (PEEK), aPolyEtherKetoneKetone (PEKK), a PolyEther EtherKetone (PEEK), anultra-high-molecular-weight polyethylene (UHMWPE), a thermoplasticpolymer as set forth in Table 1, a combination thereof or an equivalentmaterial thereof,

and wherein at least a portion of, or part of, or substantially all, orall of, the surface area of the biocompatible surface comprises or iscovered or coated by a structure or structures comprising:

(a) (i) a biocompatible material, which optionally comprises a metal ora metal alloy, and/or a stainless steel or a ceramic, and optionally themetal or a metal alloy comprises Ti, Zr, Hf, Nb, Ta, Mo and/or W metalmaterial, a Ti, Zr, Hf, Nb, Ta, Mo and/or W alloy, a Ti, Zr, Hf, Nb, Ta,Mo and/or W oxide or nitride;

-   -   (ii) a plurality of nanotubular structures that are between        about 70 to 200 nanometers (nm) in diameter, or between about 60        to 150 nm in diameter, or about 60, 65, 70, 75, 80, 85, 90, 95,        100, 105, 110, 115, 120, 125, 130, 135, 145, 150 155, 165, 170,        175, 180, 185, 190, 200 or more nanometers (nm) in diameter,    -   (iii) a plurality of nanowires, nano-lines or nano-grooves        having a spacing of between about 70 to 200 nanometers (nm), or        between about 60 to 150 nm, or alternatively between about 5 to        15 nm diameter, or between about 5 to 150 nm in diameter, or        about 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120,        125, 130, 135, 145, 150 155, 165, 170, 175, 180, 185, 190, 200        or more nanometers (nm) in diameter, or    -   (iv) a combination of the nanotubular structures of (ii) and the        nanowires, nano-lines or nano-grooves of (iii);

(b) the product of manufacture of (a), wherein a portion of, or all of,the nanotubular structures comprise nanotubes;

(c) the product of manufacture of (a) or (b), wherein the nanotubularstructures, nanowires, nano-lines or nano-grooves comprise a metal or ametal alloy, and/or a stainless steel or a ceramic, and/or thebiocompatible surface comprises a metal or a metal alloy, and/or astainless steel or a ceramic, or a polymer;

(d) the product of manufacture of (c), wherein the metal or a metalalloy comprises Ti, Zr, Hf, Nb, Ta, Mo and/or W metal material, a Ti,Zr, Hf, Nb, Ta, Mo and/or W alloy, a Ti, Zr, Hf, Nb, Ta, Mo and/or Woxide or nitride;

(e) the product of manufacture of any of (a) to (d), wherein thenanotubular structures, nanowires, nano-lines or nano-grooves arestraight, curved and/or bent, and optionally the nanotubular structures,nanowires, nano-lines or nano-grooves are fixed or loosely placed, or acombination thereof, on the biocompatible surface;

(f) the product of manufacture of any of (a) to (e), wherein at least aportion of, or all of, the nanotubular structures, nanowires, nano-linesand/or nano-grooves are arranged as an array, and optionally thenanotubular structures, nanowires, nano-lines and/or nano-grooves arearranged as three-dimensional network scaffolds;

(g) the product of manufacture of any of (a) to (f), wherein at least aportion of, or all of, the nanotubular structures, nanowires, nano-linesor nano-grooves comprise a cell, wherein optionally the cell is suitablefor implantation and/or regeneration of a bone and/or a joint tissue ina subject, and optionally the cell is an osteoblast, a stem cell or amesenchymal stem cell (MSC);

(h) the product of manufacture of any of (a) to (g), wherein at least aportion of, or all of, the nanotubular structures, nanowires, nano-linesor nano-grooves comprise one or more biologically active agents, or anosteogenic inducing agent, or a therapeutic drug, a growth factor, aprotein, an enzyme, a hormone, a nucleic acid, an RNA, a DNA, a gene, avector, a phage, an antibiotic, an antibody, a small molecule, aradioisotope, a magnetic nanoparticle and/or a particle;

(i) the product of manufacture of any of (a) to (h), wherein thenanotubular structures, nanowires, nano-lines or nano-grooves arebetween about 70 to 200 nanometers (nm) in diameter or width, or betweenabout 60 to 150 nm in diameter or width, or have a spacing between thenanowires, nano-lines or nano-grooves of between about 70 to 200nanometers (nm), or between about 60 to 150 nm, or about 60, 65, 70, 75,80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 145, 150 155,165, 170, 175, 180, 185, 190, 200 or more nanometers (nm) in diameter orwidth; and optionally comprise a mesenchymal stem cell (MSC) or a humanmesenchymal stem cell (hMSC); or embryonic stem cell, or

(j) the product of manufacture of any of (a) to (h), wherein thenanotubular structures, nanowires, nano-lines or nano-grooves are about100 nanometers (nm) in diameter or width, or are between about 80 to 120nm in diameter or width, or have a spacing between the nanowires,nano-lines or nano-grooves of about 100 nanometers (nm), or have aspacing between them of about 80 to 120 nm, or having a spacing betweenthem of about 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120,125, 130, 135, 145, 150 155, 165, 170, 175, 180, 185, 190, 200 or morenanometers (nm); and optionally comprise a “regular” or fullydifferentiated or partially differentiated osteoblast cell, or

wherein the nanotubular structures or nanotubes have a diameter ofbetween about 5 to 15 nm range and have between about 0.1 to 3micrometer height.

In alternative embodiments of the products of manufacture of theinvention, at least about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%,73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, ormore, or all, of the biocompatible surface is covered by a plurality ofnanotubular structures, nanowires, nano-lines or nano-grooves.

In alternative embodiments of the products of manufacture of theinvention, the biocompatible surface and/or the nanotubular structures,nanowires, nano-lines or nano-grooves comprise: a matrix material; or aTi, Zr, Hf, Nb, Ta, Mo and/or W metal; or an oxide of a Ti, Zr, Hf, Nb,Ta, Mo and/or W metal; (iii) an alloy of a Ti, Zr, Hf, Nb, Ta, Mo and/orW metal; or a Si, a Si oxide, an Al, an Al oxide, a carbon, a diamond, anoble metal, an Au, an Ag, a Pt and/or an Al, Au, an Ag, a Pt alloy, apolymer or a plastic material, a composite metal, a ceramic, a polymerand/or a combination thereof.

In alternative embodiments products of manufacture of the inventionfurther comprise a bone cell, a liver cell, a kidney cell, a bloodvessel cell, a skin cells, a periodontal cell or a periodontal tissuecell, a stem cell, an organ cell, or wherein the cell is a bone cell, aliver cell, a kidney cell, a blood vessel cell, a skin cells, an organcell; or,

further comprise a plurality of cells, wherein the cells comprise bonecells, liver cells, liver parenchymal cells, endothelial cells,adipocytes, fibroblastic cells, Kupffer cells, kidney cells, bloodvessel cells, skin cells, periodontal cells, odontoblasts,dentinoblasts, cementoblasts, enameloblasts, odontogenic ectomesenchymaltissue, osteoblasts, osteoclasts, fibroblasts, and other cells andtissues involved in odontogenesis or bone formation and/or stem cells,and other human or animal organ cells, or the cells are embryonic oradult stem cells, or a combination thereof. The cell can be a human oran animal cell, or the product of manufacture, further comprises a humanor an animal cell.

In alternative embodiments products of manufacture of the inventionfurther comprise a hydroxyapatite, a bio-degradable polymer, or abio-compatible or bio-inert bone cement; or further comprise abiological agent or a therapeutic composition, or an osteogenic inducingagent, or a growth factor, a collagen, a nucleic acid, an antibiotic, ahormone, a drug, a magnetic particle, a metallic particle, a ceramicparticle, a polymer particle and/or a drug delivery particle.

In alternative embodiments products of manufacture of the inventionfurther comprise nanotubular structures or nanotubes made, e.g., byanodization or by patterned chemical etching or a combination thereof.

In alternative embodiments products of manufacture of the inventionfurther comprise a nanodepot comprising a metallic or oxide material,hydroxyapatite, a bio-degradable polymer, or a bio-compatible orbio-inert bone cement; or further comprise, or comprise an osteogenicinducing agent, or a biological agent or a therapeutic composition, or agrowth factor, a collagen, a nucleic acid, an antibiotic, a hormone, adrug, a magnetic particle, a metallic particle, a ceramic particle, apolymer particle and/or a drug delivery particle.

In alternative embodiments products of manufacture of the inventionfurther comprise a matrix material comprising a nanodepot, or ananodepot, made of (comprising a) metal, oxide, hydroxyapatite,bio-degradable polymer, bio-compatible or bio-inert bone cement, whereinone or more of components selected from a list of the stem cells,osteogenic inducing agent, or the biological agent or therapeuticcomposition, or growth factor, collagen, nucleic acid, antibiotic,hormone, drug, magnetic particle, metallic particle, ceramic particle,polymer particle or drug delivery particle are stored in a nanotubularstructure or a nanotube cavity, or are stored in spacing betweenadjacent nanotubular structures, nanowires, nano-lines or nano-grooves.

The invention provides compositions and/or delivery devices comprising aproduct of manufacture of the invention, wherein optionally thecomposition and/or delivery device comprises a hydroxyapatite, abio-degradable polymer, or a bio-compatible or bio-inert bone cement; orfurther comprises, or comprises stem cells, an osteogenic inducingagent, or a biological agent or a therapeutic composition, or a growthfactor, a collagen, a nucleic acid, an antibiotic, a hormone, a drug, amagnetic particle, a metallic particle, a ceramic particle, a polymerparticle and/or a drug delivery particle.

The invention provides medical implants or replacements, orthopedic(orthopedic) or joint implants or replacements or dental implants orreplacements comprising a product of manufacture of the invention, andoptionally the orthopedic (orthopedic) or joint implant or replacementor dental implant or replacement comprises a plurality of cells, andoptionally the joint implant is a knee, hip or shoulder implant orreplacement, and optionally the cells comprise bone cells, liver cells,liver parenchymal cells, endothelial cells, adipocytes, fibroblasticcells, Kupffer cells, kidney cells, blood vessel cells, skin cells,periodontal cells, odontoblasts, dentinoblasts, cementoblasts,enameloblasts, odontogenic ectomesenchymal tissue, osteoblasts,osteoclasts, fibroblasts, and other cells and tissues involved inodontogenesis or bone formation and/or stem cells, and other human oranimal organ cells, or the cells are embryonic or adult stem cells, or acombination thereof.

The invention provides methods for inducing, enhancing and/or prolongingthe bone-forming capacity of a “regular”, or a fully differentiated or apartially differentiated osteoblast cell or cell of osteogenic lineage,comprising implanting, growing and/or culturing an osteoblast cell or acell of osteogenic lineage in a product of manufacture of the invention.

The invention provides methods for selectively releasing a therapeutic,an imaging, a drug or a biological agent in a subject, the methodcomprising

(a) implanting a product of manufacture of the invention, in a subject,wherein the product of manufacture comprises a therapeutic, an imaging,a drug or a biological agent in a liquid or colloidal composition; and,

(b) contacting the product of manufacture with ultrasonic or magneticagitation of the liquid or colloidal composition, wherein the biologicalagent is released from the product of manufacture;

and optionally the magnetic nanoparticle is selected from the groupconsisting of iron-oxide particles of magnetite (Fe₃O₄) or maghemite(γ-Fe2O3), and optionally the magnetic nanoparticle is about 5 to 50 nmin average diameter.

The invention provides products of manufacture of the invention,fabricated for in vivo hard tissue applications, which optionally can befor orthopedics, joint replacements, hip stems, knee implants, shoulderreplacements, dental implants, craniofacial implants; and for spineapplications, cervical, thoracic, and/or lumbar spinal instrumentation,interbody vertebral cages, pedicle screws and the like.

The invention provides products of manufacture of the invention,fabricated for in vivo applications including trauma, fixation devices,which optionally can be for internal, external or rods. The inventionprovides products of manufacture of the invention, fabricated for invivo applications, which optionally can be fabricated as a bonesubstitute material, bone void filler, and/or bone graft material.

The invention provides products of manufacture of the invention,fabricated for in vivo soft tissue applications, which optionally can befor catheters that need to be anchored in skin, implantable devices thatpromote cell growth, and/or biosensors that reduce fibrotic capsulewhich blocks electrical/chemical signal.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

All publications, patents, patent applications, GenBank sequences andATCC deposits, cited herein are hereby expressly incorporated byreference for all purposes.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are illustrative of embodiments of the invention and arenot meant to limit the scope of the invention as encompassed by theclaims. The advantages, nature and additional features of the inventionwill appear more fully upon consideration of the illustrativeembodiments described in the accompanying drawings.

FIG. 1 illustrates enhanced osteoblast cell adhesion and growth onconformationally placed TiO₂ nanotubes by anodization of deposited Tilayer on unpatterned or patterned thermoplastic polymer, PolyEtherEtherKetone (PEEK), PolyEtherKetoneKetone (PEKK), anultra-high-molecular-weight polyethylene (UHMWPE), thermoplastic polymeras set forth in Table 1, any combination thereof or equivalent materialthereof (although only PEEK and UHMWPE are illustrated) (flat orthree-dimensionally shaped) or various other polymer or glass surface.

FIG. 2A-C illustrate Nano-patterned PEEK, PEKK, UHMWPE, thermoplasticpolymer as set forth in Table 1, any combination thereof or equivalentmaterial thereof (although only PEEK is illustrated)+cell-growthenhancing coating of Ti or TiO₂ coating or other layer coating. FIG. 2Aillustrates an exemplary mould (stamp) for nano-imprinting afterthermoplastic heating (or coat with UV-sensitive resist and imprintpattern (protruding or recessed), and a nano-imprinted PEEK or otherbiocompatible polymers like UHMWPE; FIG. 2B illustrates deposited Ti,Ti0₂, Zr0₂, Hf0₂, Ta, Ta-oxide or other cell-growth enhancing coating(by sputtering, plasma spray, CVD deposition) on PEEK surface. The Tisurface may optionally anodized or nano-patterned into Ti0₂ nanotubesfor enhanced cell adhesion/growth or stem cell control; FIG. 2Cillustrates osteoblast, stem cells or other cells (or bone, cartilagetissue) adhered and growing on Ti coated (or Co—Cr or otherbiocompatible metal or ceramic), imprint patterned PEEK or UHMWPEsurface.

FIG. 3A-C illustrate surface-modified PEEK, PEKK, UHMWPE, thermoplasticpolymer as set forth in Table 1, any combination thereof or equivalentmaterial thereof (although only PEEK is illustrated) with nano-imprintedpattern coated with Ti, Zr, etc., and anodized to form conformalnanotubes. FIG. 3A illustrates a nano-imprinted PEEK or otherbiocompatible polymer with a deposited Ti or other cell-growth enhancingcoating (e.g., by sputtering, plasma spray, CVD deposition) on apatterned or flat PEEK surface; FIG. 3B illustrates anodized Ti0₂nanotubes on a Ti-deposited surface on a PEEK substrate; FIG. 3Cillustrates osteoblasts, stem cells or other cells (or bone or cartilagetissue) adhered and growing on Ti0₂ nanotubes.

FIG. 4A-E illustrate an exemplary three dimensional complexnano-imprinting and surface coating with Ti or Ti0₂ nanotubes: FIG. 4(a)illustrates an exemplary three-dimensional mould for nano-imprinting ofcomplex geometry onto PEEK or other biocompatible polymer materials likeor UHMWPE to exhibit nanosurface structure; FIG. 4(b) illustrates anexemplary nano-imprinted+Ti coated or Ta coated by sputtering orevaporation (or additionally anodized or hydrothermal treated for Ti0₂nanotube surface) for enhanced cell adhesion and growth, or stem cellcontrol); FIG. 4(c) illustrates an example SEM micrograph showingapproximately 80 to 100 nm diameter Ti0₂ nanotubes grown by anodizationof deposited Ti coating; FIG. 4(d) illustrates exemplary 8 nm diameterTi0₂ nanotubes grown on deposited Ti film by hydrothermal process atabout 100° C. to about 150° C. (TEM image (left) and SEM image (right));FIG. 4(e) graphically illustrates alkaline phosphatase activity ofosteoblast cells cultured on smooth Ti, vs 8 nm diameter Ti0₂ nanotubesafter 24 and 48 h of incubation. The bar graphs show theaverage±standard error bars.

FIG. 5 illustrates island nanopatterned PEEK, PEKK, UHMWPE,thermoplastic polymer as set forth in Table 1, any combination thereofor equivalent material thereof (although only PEEK is illustrated) byimprinting and metal coated.

FIG. 6 illustrates line-array nanopatterned PEEK, PEKK, UHMWPE,thermoplastic polymer as set forth in Table 1, any combination thereofor equivalent material thereof (although only PEEK is illustrated) byimprinting and metal coated.

FIG. 7 illustrates island nanopatterned PEEK, PEKK, UHMWPE,thermoplastic polymer as set forth in Table 1, any combination thereofor equivalent material thereof (although only PEEK is illustrated) byimprinting and Ti metal coated for Ti0₂ nanotube anodization.

FIG. 8 illustrates a 48 hour culture with mouse osteoblast cells(MCT3-E1) on PEEK substrate with no patterning, as discussed in detail,below.

FIG. 9 illustrates osteoblast cell growth and spreading on 20 nm TiCoated PEEK, as discussed in detail, below.

FIG. 10 graphically illustrates data showing the comparative osteoblastcell density over 48 hours (hrs), as discussed in detail, below.

FIG. 11 graphically illustrates data showing the comparative osteoblastcell density after cell culture on flat unpatterned PEEK+Ti coated,versus (vs) nano-imprinted patterned PEEK+Ti coated shown at a 48 Hrscell culture period, as discussed in detail, below.

FIG. 12 illustrates an image of TiO₂ nanotubes/nanopores formed byanodization on sputter coated, 1 μm thick Ti film on flat commercialPEEK, as discussed in detail, below.

FIG. 13 illustrates osteoblast cell growth and spreading on TiO2nanotube coated PEEK at 24 hrs culture, as discussed in detail, below.

FIG. 14 illustrates an image of PEEK and Titanium (Ti) implant materialsin Porcine Rib; sample size about 2.5×2.5 cm; note—the horizontal linein the middle of some samples is just the folding line in the PEEK, asdiscussed in detail, below.

FIG. 15 illustrates an X-ray image showing that the Ti coated PEEKimplants are radiolucent, as discussed in detail, below.

FIG. 16(a) illustrates three-dimensionally imprinted surface of a PEEK,PEKK, UHMWPE, thermoplastic polymer as set forth in Table 1, anycombination thereof or equivalent material thereof, implant usingsideway-split or upper versus lower split imprint stamps; FIG. 16(b)illustrates both the inside and the outside of the complex shapedimparts made of PEEK, PEKK, UHMWPE, etc., coated with a Ti or a Ta orother refractory metal and/or their oxide(s) for bioactivity; and in oneembodiment a probe-shaped sputter or evaporator target can be insertedinto the cavity geometry.

FIG. 17A-C illustrate exemplary “re-entrant” Ti or TiO₂ coating: FIG.17(a) illustrates PEEK, PEKK, UHMWPE, etc. implant with surface pores(in alternative embodiment made by warm imprinting, sand blasting,masked etching, and the like); FIG. 17(b) illustrates the (optional)embodiment comprising plastic deformation to partially squash thepolymer implant surface and induce re-entrant pore geometry on PEEK,PEKK, UHMWPE, etc.; FIG. 17(c) illustrates Ti, Ta, Zr, Hf, or theiroxides, and the like, coating on re-entrant shape pore surface forenhanced mechanical locking.

The drawings are further described below.

It is to be understood that the drawings are for purposes ofillustrating the concepts of the invention and are not to scale.

DETAILED DESCRIPTION

In alternative embodiments, the invention provides surface-nanopatternedpolymers for e.g., joint (e.g., knee, hip and shoulder) replacement,bone or tooth reconstructive and/or implant applications, and the like,comprising a PolyEther EtherKetone (PEEK), a PolyEtherKetoneKetone(PEKK), a PolyEther EtherKetone (PEEK) or an ultra-high-molecular-weightpolyethylene (UHMWPE), or equivalent, or a combination thereof, materialsurface-modified (surface-nanopatterned) to exhibit nanostructuredsurfaces that promote osseointegration and bond-bonding.

In alternative embodiments, PEEK, PEKK or UHMWPE surface modification isdone by coating the polymer with layers of Ti or Ti oxide, or similarbiocompatible metals, alloys and oxides which are nanostructured byvarious means (e.g., nano-imprinting, patterned-mask-deposition followedby preferential etching or sand blasting etc). Whereas polymersintegrate poorly with bone, the invention's nanostructured coatingenhances cell adhesion and promotes preferential stem celldifferentiation to bone cells. The invention thus enables use ofelastically bone-like and x-ray translucent PEEK for knee prostheses andother joint replacements or bone-anchored implants, e.g., hip andshoulder replacements, dental implants.

In alternative embodiments, products of manufacture of the inventionimprove the osseointegration of PEEK implants by chemical and structuralmodifications of its surface. In alternative embodiments, the inventionprovides a chemically and/or microstructurally modified PEEK surfacewith a strongly adherent coating to the PEEK surface substrate that hasfavorable interfacial bonding properties with bone.

In alternative embodiments, products of manufacture of the inventioncomprise a thermoplastic polymer such as PEEK, e.g., DYNEEMA™ (DSMDyneema LLC, Stanley, NC) or SPECTRA™ (Honeywell, Colonial Heights,Va.), or any of the thermoplastic polymers listed below, and are made tocomprise a nanostructured surface modification which promotesosseointegration.

TABLE 1 Exemplary thermoplastics used to make products of manufacture ofthe invention Acrylonitrile butadiene styrene (ABS) Acrylic (PMMA)Celluloid Cellulose acetate Cycloolefin Copolymer (COC) Ethylene-VinylAcetate (EVA) Ethylene vinyl alcohol (EVOH) Fluoroplastics (PTFE,alongside with FEP, PFA, CTFE, ECTFE, ETFE) Ionomers Kydex ™, atrademarked acrylic/PVC alloy Liquid Crystal Polymer (LCP) Polyacetal(POM or Acetal) Polyacrylates (Acrylic) Polyacrylonitrile (PAN orAcrylonitrile) Polyamide (PA or Nylon) Polyamide-imide (PAI)Polyaryletherketone (PAEK or Ketone) Polybutadiene (PBD) Polybutylene(PB) Polybutylene terephthalate (PBT) Polycaprolactone (PCL)Polychlorotrifluoroethylene (PCTFE) Polyethylene terephthalate (PET)Polycyclohexylene dimethylene terephthalate (PCT) Polycarbonate (PC)Polyhydroxyalkanoates (PHAs) Polyketone (PK) Polyester Polyethylene (PE)Polyetheretherketone (PEEK) Polyetherketoneketone (PEKK) Polyetherimide(PEI) Polyethersulfone (PES) Polysulfone Polyethylenechlorinates (PEC)Polyimide (PI) Polylactic acid (PLA) Polymethylpentene (PMP)Polyphenylene oxide (PPO) Polyphenylene sulfide (PPS) Polyphthalamide(PPA) Polypropylene (PP) Polystyrene (PS) Polysulfone (PSU)Polytrimethylene terephthalate (PTT) Polyurethane (PU) Polyvinyl acetate(PVA) Polyvinyl chloride (PVC) Polyvinylidene chloride (PVDC)Styrene-acrylonitrile (SAN)

In alternative embodiments, products of manufacture of the inventioncomprise a thermoplastic polymer such as an ultra-high-molecular-weightpolyethylene (UHMWPE). This polymer can be surface modified in a similarway as a PEEK; it is a strong but a thermoplastic polymer that can besoftened at about 140° C. for nano-imprinting. UHMWPE (which can beshortened to UHMW), is also known as high-modulus polyethylene (HMPE) orhigh-performance polyethylene (HPPE), thus reference to UHMWPE alsoincludes any UHMW, HMPE, HPPE or equivalent. In alternative embodiments,thermoplastic polymers with long chains having molecular weightsnumbering in the millions, e.g., between 2 and 6 million daltons, areused. In alternative embodiments, HDPE molecules can have between 700and 1,800 monomer units per molecule, whereas UHMWPE molecules can have100,000 to 250,000 monomers each.

In alternative embodiments, products of manufacture of the invention aremade by nano-imprinting or patterned-mask-deposition followed bypreferential etching of exposed surface (e.g., using reactive ion etchor chemical etch), or mechanical sand blasting or shot pinning can beutilized.

In alternative embodiments of products of manufacture of the inventionthe thermoplastic polymer (e.g., a PEEK or UHMWPE) bonds and integrateswith bone. For example, in one embodiment an entire knee prostheticcomprises a PEEK or a UHMWPE, with the backside of the nanostructuredimplant surface-modified to promote bone bonding, and the front side ofthe implant designed as an articulating joint surface.

In alternative embodiments, protruding or recessed nanostructures (FIG.1, FIG. 2, FIG. 3 and FIG. 4) of nanopillars, nanopores or nanotubesenhance cell adhesion, and also promotes preferential stem celldifferentiation to bone cells. For example, in one embodiment,mesenchymal stem cells are used such that they differentiate toosteoblast cells in a Ti nanotube environment.

As illustrated in FIG. 4, eight (8) nm diameter TiO₂ nanotubes preparedby hydrothermal process have excellent bone cell growth characteristics,as good as anodized approximately 100 nm diameter vertically alignedTiO2 nanotubes; see the 8 nm TiO2 nanotube data as FIG. 4(d) and FIG.4(e), comparing with anodized ˜100 nm TiO2 nanotubes in FIG. 4(c). Asillustrated in FIG. 4(e), the 8 nm diameter nanotube structure providedsignificantly up-regulated bone forming ability from the MC3T3-E1 mouseosteoblast bone cells with approximately 2 to 3 fold increased alkalinephosphatase (ALP) activity levels, and induced the formation of abundantamounts of bone matrix deposition predominantly consisting of calciumand phosphorous. FIG. 4 illustrates three dimensional complexnano-imprinting and surface coating with Ti or TiO₂ nanotubes: (a)Three-dimensional mould for nano-imprinting of complex geometry ontoPEEK or other biocompatible polymer materials like or UHMWPE to exhibitnano surface structure; (b) Nano-imprinted+Ti coated or Ta coated bysputtering or evaporation (or additionally anodized or hydrothermaltreated for TiO₂ nanotube surface) for enhanced cell adhesion andgrowth, or stem cell control); (c) Example SEM micrograph showing about80-100 nm diameter TiO₂ nanotubes grown by anodization of deposited Ticoating; (d) Example 8 nm diameter TiO₂ nanotubes grown on deposited Tifilm by hydrothermal process at about 100° C. to about 150° C. (TEMimage (left) and SEM image (right)); (e) Alkaline phosphatase activityof osteoblast cells cultured on smooth Ti, vs 8 nm diameter TiO₂nanotubes after 24 and 48 h of incubation. The bar graphs show theaverage±standard error bars. The 8 nm diameter nanotube structureprovided significantly up-regulated bone forming ability from theMC3T3-E1 mouse osteoblast bone cells with about 2 to 3 fold increasedalkaline phosphatase (ALP) activity levels, and induced the formation ofabundant amounts of bone matrix deposition predominantly consisting ofcalcium and phosphorous.

Alternatively, these anodized or hydrothermally grown nanotubes can beoptionally micro or macro patterned so that 50% or less of the surfacearea of PEEK or UHMWPE is covered by TiO₂ nanotubes for enhanced x-rayradiolucent properties.

In alternative embodiments, surface nanostructured thermoplasticpolymers (e.g., a PEEK or UHMWPE) of the invention have a coating, or anadditional coating, with a Ti and Ti oxide, Zr, Hf, Nb, Ta, Mo, W, Cr,Cr—Co alloy, stainless steel and their oxides, as well as their alloys,with a thin layer having a thickness of at least 5 nm, and optionallyless than 500 nm, so that much of some x-ray penetration with soft x-rayis possible for diagnostic/tracking purposes. These surface coatinglayers of Ti and Ti oxide, Zr, Hf, Nb, Ta, Mo, W, Cr, Cr—Co alloy,stainless steel and their oxides, as well as their alloys, are bioactiveand enhance osseointegration and stem cell differentiation to bonecells.

An alternative embodiment configuration of the invention is to introducepartially Ti covered surface (or other adherent coating materials), forexample, about 20% to 70% of the relevant implant surface is coated withosseointegrating metal film coating, with the remaining 80% to 30% are abare-surface thermoplastic polymer (e.g., a PEEK or UHMWPE) to providesoft x-ray imaging of the regions with the implants to monitor thesoundness of positioning, attachment and osseointegration progress.Examples of nanopatterned PEEK or UHMWPE or equivalents with added Ticoating are shown in SEM micrographs of FIG. 5, FIG. 6 and FIG. 7.

In alternative embodiments of products of manufacture of the inventionthe thermoplastic polymer (e.g., a PEEK) comprises a surface of, orfurther comprise an additional nanostructure on a deposited metal layer,including e.g., Ti (or Zr, Hf, Nb, Ta, Mo, W, Cr, and their alloys,Cr—Co alloy, stainless steel), e.g., by using anodization for TiO₂nanotubes or alloy nanotubes having a dimension of about 20-1000 nmdiameter and relatively thin (e.g., about 30-500 nm height) nanotubelayer for enhanced soft x-ray imaging. In alternative embodiments thepresence of anodized TiO₂ nanotubes significantly enhances theosseointegration kinetics and the bone-bonding mechanical strength.

In alternative embodiments, nanopillar or nanopore structure, instead ofor in addition to, nanotube structures, are fabricated using e.g., amask-patterned surface modification.

In alternative embodiments, products of manufacture of the inventioncomprise a metal- or ceramic-coated surface (e.g., a PEEK or a UHMWPEsurface). embodiments of products of manufacture the anodized surfacecan partially cover the relevant implant surface, for example, about20-70% of the surface can be coated with an osseointegrating nanotubelayer, with the remaining about 80-30% bare surface of the thermoplasticpolymer (e.g., a PEEK or a UHMWPE) provides soft x-ray imaging of theregions with the implants for monitoring or diagnosis purpose.

In alternative embodiments, products of manufacture of the inventioncomprise a nanotube pore structure (or the spacing and gap between thenanopillar structures) to store and controllably release biologicalagents such as stem cells, growth factors (such as bone morphogenicprotein), DNA or RNA, antibiotics, or various drugs, and allow them tobe slowly released, or remote activated for on-demand release.

In alternative embodiments, products of manufacture of the inventioncomprise thermoplastic polymer (e.g., a PEEK or a UHMWPE)osseointegration-promoting surface on a joint replacement prosthesis orimplant, e.g., a knee, hip and shoulder replacement or implantprostheses, or for any joint replacement or bone-anchored implant, e.g.,hip and shoulder replacements, dental implants.

In alternative embodiments, products of manufacture of the invention aremade utilizing a novel nano-patterned imprinting stamp which, whenplaced vertically and impressed with compressive force onto the surfaceof thermoplastic biomaterials. One example comprises a PEEK near itsglass transition temperature (˜143° C.), which produces a nano-patternedpillar array or pore array. In alternative embodiments, dimensions ofthe resultant nano-pillars are in the range of between about 10 to about5000 nm, or between about 70 to about 1000 nm, or between about 100 toabout 700 nm.

In alternative embodiments, after nano-imprinting of the polymerbiomaterial, the nano-patterned PEEK, or UHMWPE or equivalents is/aresubjected to Scanning Electron Microscopy (SEM) to verify thenanostructures. Then, optionally, a layer of titanium (or Ti oxide,either amorphous, anatase or rutile phase) is sputter coated uniformlyonto the nano-patterned surface.

In alternative embodiments, the layer of titanium is varied between 5 nmand 500 nm. The titanium layer can serve a two-fold purpose. First, itcoats the hydrophobic thermoplastic polymer (e.g., a PEEK or UHMWPE orequivalents) with a layer of titanium which is both hydrophilic andbiocompatible. Second, depending on the thickness of the titaniumcoating, it allows for additional surface modifications that promoteenhanced osseointegration on the titanium coated nanostructured pattern.For example in alternative embodiments an additional surfacemodification is anodization in hydrofluoric acid for 30 minutes at 20volts to fabricate titanium dioxide nanotubes on the surface for anenhanced osseointegration effect.

In alternative embodiments, products of manufacture of the inventioncomprise or are fabricated for in vivo hard tissue applications,including e.g., orthopedics, joint replacements, hip stems, kneeimplants, shoulder replacements, dental implants, craniofacial implants;and for spine applications, cervical, thoracic, and/or lumbar spinalinstrumentation, interbody vertebral cages, pedicle screws and the like.In alternative embodiments, products of manufacture of the inventioncomprise or are fabricated for in vivo applications including trauma,fixation devices including internal, external or rods. In alternativeembodiments, products of manufacture of the invention comprise or arefabricated for in vivo applications as bone substitute material, bonevoid filler, and/or bone grafts.

In alternative embodiments, products of manufacture of the inventioncomprise or are fabricated for in vivo soft tissue applications,including e.g., catheters that need to be anchored in skin, implantabledevices that promote cell growth, biosensors that reduce fibroticcapsule which blocks electrical/chemical signal.

FIG. 8 illustrates that there was low osteoblast viability and poor cellspreading on as-received commercial PEEK substrate with no patterningand no Ti coating. FIG. 8 shows a 48 hour culture with mouse osteoblastcells (MCT3-E1) on PEEK substrate with no patterning. All the PEEKsamples for this study was procured from Plastics International. ThePEEK samples used for the experiments were 0.25 inch thick sheet form.No obvious cell adhesion and growth observed on PEEK surface, eitherflat or patterned.

FIG. 9 illustrates osteoblast cell growth and spreading on 20 nm TiCoated PEEK; PEEK was nanoimprinted at 400 nm diameter and 100 nmheight+20 nm Ti sputter coated. Mouse osteoblast cell at 48 hrs cultureperiod were used. No cell adhesion or growth on PEEK, no cell adhesionor growth on flat Ti coated PEEK, but lots of osteoblast cells areobserved adhering/growing on 20 nm Ti coated, nano-patterned PEEK.

FIG. 10 illustrates data showing the comparative osteoblast cell densityover 48 hours (hrs); the MTT assay measured cell viability as opticaldensity; unpatterned PEEK (flat) vs nano-imprinted pattern shown.

FIG. 11 illustrates data showing the comparative osteoblast cell densityafter cell culture; Flat unpatterned PEEK+Ti coated, versus (vs)nano-imprinted patterned PEEK+Ti coated shown at a 48 Hrs cell cultureperiod.

In alternative embodiments, a “patterned PEEK” design has clinicalapplications, e.g., in orthopedics. In alternative embodiments,patterned PEEK with a Ti coating yielded highly favorable osteoblastcell viability and cell spreading. 20 nm Ti thickness performed betterthan 5 nm Ti layer; cells preferred the patterned surfaces to the flatsurface.

FIG. 12 illustrates an image of TiO₂ nanotubes/nanopores formed byanodization on sputter coated, 1 μm thick Ti film on flat commercialPEEK. Flat Ti film alone on PEEK did not provide much osteoblast celladhesion and growth, TiO2 nanotube/nanopore formation induced strongcell adhesion.

FIG. 13 illustrates osteoblast cell growth and spreading on TiO2nanotube coated PEEK at 24 hrs culture; the figure shows FDA stainingunder fluorescent microscopy at a 24 hour time point. For TiO2 nanotubeformation from the Ti film added on the PEEK surface, the Ti coated PEEK(approximately 1 micrometer thick Ti sputter coated) was anodized in anethylene glycol based solution (0.3 wt. % ammonium fluoride (NH4F) and 2vol % water). The anodization was done at 20 V for a 30 minute duration.The samples were then cut into 0.5 cm×0.5 cm squares and seeded withMCT3-E1 mouse osteoblast cells at passage 7. Each sample received 1milliliter containing 50,000 cells in osteogenic media. Osteoblast cellviability was evaluated at 24 hr and 48 hr timepoints with an MTT assayand FDA staining for fluorescent microscopy.

In one embodiment, nano-patterned PEEK coated with titanium isradiolucent (partly transparent to medical X-ray). In general, X-raysfrom about 0.12 to 12 keV (10 to 0.10 nm wavelength) are classified as“soft” X-rays, and from about 12 to 120 keV (0.10 to 0.010 nmwavelength) as “hard” X-rays, due to their penetrating abilities. Weutilized 18 keV X-ray, slightly penetrating x-ray suitable for medicaluses.

FIG. 14 illustrates an image of PEEK and Titanium (Ti) implant materialsin Porcine Rib; sample size about 2.5×2.5 cm; note—the horizontal linein the middle of some samples is just the folding line in the PEEK.

FIG. 15 illustrates an X-ray image showing that the Ti coated PEEKimplants are radiolucent.

In alternative embodiments, nano-patterned PEEK with a 5 nm or 20 nmlayer of titanium is radiolucent, and allows x-ray analysis of implantstructures and its evolution in vivo or in patients having theinventive, improved PEEK implants. Radiolucency is an importantbiomaterial property for unobstructed visualization during implantationand post-surgical evaluation for best patient care practices.

In alternative embodiments, the invention provides interbody fusioncages comprising nano-patterned PEEK, e.g. as illustrated in FIG. 16,which illustrates an interbody fusion cage by Interbody Innovations,Midland, Tex.

In alternative embodiments, the invention provides nano-patterned PEEKthat is radiolucent and has a similar modulus of elasticity to bone;these embodiments have a number of applications in orthopedics, trauma,and even for soft tissue applications.

In alternative embodiments, the invention provides nano-patterned PEEKfor orthopedic joint replacements, this embodiment comprises a materialwhich bonds to bone and has excellent stiffness properties. Potentialapplications for this exemplary nano-patterned PEEK include any medicaldevices which interface directly with bone including hip stems, kneeimplants, and shoulder replacements.

In alternative embodiments, the invention provides nano-patterned PEEKfor craniofacial implants; these nano-patterned PEEK of the inventioncan be used for maxillofacial clinical applications where anosseoinductive material is desired. This includes oral implants,especially for applications in the lower jaw where bone density is poor.

In alternative embodiments, the invention provides nano-patterned PEEKfor spinal applications, e.g., as an interbody support cage which canprovide mechanical support between in the cervical, thoracic, and lumbarvertebrates.

In alternative embodiments, the invention provides nano-patterned PEEKfor applications in the spine, e.g. including spinal fixation devices(i.e. pedical screws, rods, other support structures) where bonding isdesired to bone for permanent anchorage.

In alternative embodiments, the invention provides nano-patterned PEEKfor use in trauma, where rapid healing and bonding to bone is desired.This includes both internal and external fixation devices to fix brokenbones. In alternative embodiments, the invention provides nano-patternedPEEK for areas of trauma that are quickly growing, e.g. for militaryapplications where wounded soldiers can recover quicker from orthopedicinjuries.

In alternative embodiments, the invention provides nano-patterned PEEKfor soft tissue applications, e.g., where PEEK is beginning to be usedfor soft tissue repair in arthroscopy because the polymer has morefavorable properties with soft tissue than metal. In alternativeembodiments, with favorable cell growth properties, nano-patterned PEEKof the invention can enhance biocompatibility and overall tissueintegration of devices.

In alternative embodiments, the invention provides nano-patterned PEEKinclude nano-patterned, thin metallized PEEK for use e.g. in catheters,devices which penetrate the skin, and coatings for biosensors forimproved signal readings with less fibrotic encapsulation.

FIG. 16 illustrates: (a) Three-dimensionally imprinted surface of PEEKor UHMWPE implant (using sideway-split, or upper vs lower split imprintstamps), (b) Both inside and outside of the complex shaped implant partsmade of PEEK or UHMWPE are coated with Ti or Ta (or other refractorymetals and their oxides) for bioactivity, using a probe shaped sputteror evaporator target that can be inserted into the cavity geometry.

In alternative embodiments, these anodized or hydrothermally grownnanotubes grown on deposited Ti film on PEEK, UHMWPE or other polymerimplant surface are micro or macro patterned so that 50% or less of thesurface area of PEEK or UHMWPE is covered by TiO2 nanotubes for enhancedx-ray radiolucent properties.

Referring to FIG. 16: FIG. 16(a) illustrates a three-dimensionallyimprinted surface of an PEEK or UHMWPE implant of the invention. Inalternative embodiments, nanostructure formation on the surface ofcomplicated structures such as the vertical wall of a cavity are made(accomplished) by using sideway or vertically split dies or nano-imprintstamps, e.g., with a pair of stamps one facing the outer wall and theother facing the interior wall in FIG. 16. Shown in FIG. 16(b) is anillustration of a method for coating such interior surface (coating ofinside surface is more difficult than outer surface), e.g., using aprobe shaped sputter or evaporator target device that can be insertedinto the cavity geometry.

FIG. 17 illustrates: re-entrant Ti or TiO2 coating: (a) Peek or ultrahigh molecular weight poly ethylene (UHMWPE) implant with surface pores(e.g., made by warm imprinting, sand blasting, masked etching, etc.),(b) Optional warm compressive plastic deformation to partially squashthe polymer implant surface and induce re-entrant pore geometry on peekor UHMWPE, (c) Ti coating (or Ta, Zr, Hf coating) or their oxide versionon re-entrant shape pore surface for enhanced mechanical locking.

In alternative embodiments, it is important to ensure good adhesion ofTi and other coating layer to the PEEK and related polymer implantsurfaces. One embodiment to enhance such mechanical stability againstlayer peeling is to introduce a re-entrant pore geometry, as illustratedin FIG. 17. As the coating material such as Ti is continuous, there-entrant pore will have some effect of mechanical constraint orlocking of the film to minimize the initiation of peeling off. There-entrant pores can have an entrance diameter (an average diameter ifit is not circular) which is smaller than the maximum average diameterwithin the pore. In alternative embodiments, a ratio of the maximuminner-pore diameter to the entrance diameter is at least 1.05, or atleast 1.20.

Referring to FIG. 17, the diagram schematically illustrates an exemplarymethod of forming re-entrant pores, followed by Ti or TiO2 coating. InFIG. 17(a), a peek or ultra high molecular weight poly ethylene (UHMWPE)implant with surface pores (e.g., made by warm imprinting, sandblasting, masked etching, etc.), which is then optionally warmcompressed in the vertical direction to induce plastic deformation topartially squash the polymer implant surface and induce re-entrant poregeometry on peek or UHMWPE as illustrated in FIG. 17(b). After theformation of re-entrant pores, Ti coating (or Ta, Zr, Hf coating) or acoating of their oxide version on re-entrant shape pore surface isconducted as described in FIG. 17(c) for enhanced mechanical locking.

It should be understood that the invention can be practiced withmodification and alteration within the spirit and scope of the appendedclaims. The description is not intended to be exhaustive or to limit theinvention to the precise form disclosed. It should be understood thatthe invention can be practiced with modification and alteration and thatthe invention be limited only by the claims and the equivalents thereof.

1. A product of manufacture comprising: (a) a thermoplastic polymer; and(b) a biocompatible surface layer deposited on at least a portion of thethermoplastic polymer, wherein the biocompatible surface layer comprisesa plurality of nanotubular structures that each have a diameter ofapproximately 5 to 1000 nanometers (nm) and a height of approximately 30nm to 3 micrometer, or a height of approximately 30 nm to 500 nm.
 2. Theproduct of manufacture of claim 1, wherein at least approximately 50% ofthe biocompatible surface layer is covered by the plurality ofnanotubular structures, or substantially all of the biocompatiblesurface layer is covered by the plurality of nanotubular structures. 3.The product of manufacture of claim 1, wherein any of the biocompatiblesurface layer and the plurality of nanotubular structures comprise amaterial selected from the group consisting of: (i) a Ti, a Zr, a Hf, aNb, a Ta, a Mo and a W metal; (ii) an oxide of a Ti, a Zr, a Hf, a Nb, aTa, a Mo and a W metal; (iii) an alloy of a Ti, a Zr, a Hf, a Nb, a Ta,a Mo and a W metal; (iv) a Si, a Si oxide, an Al, an Al oxide, a carbon,a diamond, a noble metal, an Au, an Ag, a Pt, an Ag oxide, and a Ptalloy, (v) a plastic material, (vi) a composite metal, (vii) a ceramic,(vii) a polymer, and (viii) a combination thereof.
 4. The product ofmanufacture of claim 1, further comprising any of at least one of a bonecell, a liver cell, a kidney cell, a blood vessel cell, a skin cell, aperiodontal cell, a periodontal tissue cell, a stem cell, an organ cell,a fully differentiated osteoblast cell, a partially differentiatedosteoblast cell, a mesenchymal stem cell (MSC), a human mesenchymal stemcell (hMSC), an embryonic stem cell, an adult stem cell, endothelialcells, adipocytes, fibroblastic cells, Kupffer cells, odontoblasts,dentinoblasts, cementoblasts, enameloblasts, odontogenic ectomesenchymaltissue, osteoblasts, osteoclasts, fibroblasts, a cell involved inodontogenesis or bone formation, a human cell, an animal cell, and acombination thereof.
 5. The product of manufacture of claim 1, whereinthe biocompatible surface layer includes any of a hydroxyapatite, abio-degradable polymer, a bio-compatible cement, a bio-inert bonecement, a biological agent, a therapeutic composition, an osteogenicinducing agent, a growth factor, a collagen, a nucleic acid, anantibiotic, a hormone, a drug, a magnetic particle, a metallic particle,a ceramic particle, a polymer particle, a drug delivery particle, and acombination thereof.
 6. The product of manufacture of claim 1, whereinthe plurality of nanotubular structures: (a) are in the form of any ofnanowires, nano-lines, nano-grooves, nanotubes, nanopores, and acombination thereof; or (b) are made by any of anodization, patternedchemical etching, and a combination thereof.
 7. The product ofmanufacture of claim 1, wherein the plurality of nanotubular structuresand spacing between adjacent nanotubular structures act as a nanodepotthat stores any of a metal, an oxide, a hydroxyapatite, a bio-degradablepolymer, a bio-compatible, a bio-inert bone cement, a cell, a stem cell,an osteogenic inducing agent, a biological agent, a therapeuticcomposition, a growth factor, a collagen, a nucleic acid, an antibiotic,a hormone, a drug, a magnetic particle, a metallic particle, a ceramicparticle, a polymer particle, a drug delivery particle, and acombination thereof.
 8. A device comprising a product of manufacture ofclaim 1, and optionally the device is a delivery device.
 9. An implantcomprising a product of manufacture of claim 1, and optionally theimplant is any of a medical implant, an orthopedic implant, a jointimplant, a joint replacement, a dental implant, a tooth implant, a kneeimplant, a hip implant, a shoulder implant, a joint implant, a jointreplacement, a dental replacement, a tooth replacement, a kneereplacement, a hip replacement, and a shoulder replacement.
 10. Aproduct of manufacture of claim 1, fabricated for any of in vivo hardtissue applications, in vivo soft tissue applications, and in vivo hardtissue and soft tissue applications.
 11. The product of manufacture ofclaim 10, wherein the in vivo soft tissue applications include any of:use with a catheter, use with an implantable device that promotes cellgrowth, and, use with a biosensor that reduces a fibrotic capsule whichblocks any of an electrical and a chemical signal.
 12. The product ofmanufacture of claim 10, wherein the in vivo hard tissue applicationsinclude any of: an orthopedic implant, an orthopedic replacement, ajoint implant, a joint replacement, a hip stem, a knee implant, ashoulder replacement, a dental implant, a craniofacial implant; a spineapplication, a cervical instrumentation, a thoracic instrumentation, alumbar spinal instrumentation, an interbody vertebral cage, a pediclescrew, a bone substitute material, a bone void filler, a bone graftmaterial, and a combination thereof.
 13. The product of manufacture ofclaim 10, wherein the in vivo hard tissue and soft tissue applicationsinclude any of: a trauma application, a fixation device, an internalfixation device, an external fixation device, a fixation device, aninternal fixation device, an external fixation device, and a rod.
 14. Aproduct of manufacture of claim 1, fabricated for in vitro applications.15. The product of manufacture of claim 1, wherein the thermoplasticpolymer: (a) is any of a PolyEther EtherKetone (PEEK), aPolyEtherKetoneKetone (PEKK), a PolyEther EtherKetone (PEEK), anultra-high-molecular-weight polyethylene (UHMWPE), a combinationthereof, and an equivalent material thereof; or (b) comprises anano-patterned PolyEther EtherKetone (PEEK) and the biocompatiblesurface layer comprises a layer of titanium (Ti) sputtered on a surfaceof the thermoplastic polymer.
 16. The product of manufacture of claim 1,wherein the plurality of nanotubular structures: (a) comprise any of ametal, a metal alloy, a stainless steel, and a ceramic, and optionallythe metal and the metal alloy comprise any of a Ti metal, a Zr metal, aHf metal, a Nb metal, a Ta metal, a Mo metal, a W metal, a Ti alloy, aZr alloy, a Hf alloy, a Nb alloy, a Ta alloy, a Mo alloy, a W alloy, aTi oxide, a Zr oxide, a Hf oxide, a Nb oxide, a Ta oxide, a Mo oxide, aW oxide, and a nitride, (b) are any of straight, curved, and bent, orare arranged as any of an array and a three-dimensional networkscaffold; or (c) each have a diameter of approximately 60 to 150 nm; orthe plurality of nanotubular structures are approximately 100 nanometers(nm) in diameter; or the plurality of nanotubular structures areapproximately 80 to 120 nanometers (nm) in diameter; or the plurality ofnanotubular structures each has a diameter of approximately 8 nanometers(nm). 17-19. (canceled)
 20. The product of manufacture of claim 1,wherein: (a) there is a spacing between the plurality of nanotubularstructures of approximately 70 to 200 nanometers (nm); the spacingbetween the plurality of nanotubular structures is approximately 60 to150 nanometers (nm); the spacing between the plurality of nanotubularstructures is approximately 80 to 120 nanometers (nm); (b) the pluralityof nanotubular structures each have a diameter of approximately 5 to 15nm and approximately a 0.1 to 3 micrometer height; (c) the plurality ofnanotubular structures each have height of approximately 0.1 to 3micrometer; or (d) the plurality of nanotubular structures each haveheight of approximately 30 nm to 500 nm. 21-22. (canceled)
 23. Theproduct of manufacture of claim 1, wherein: (a) the thermoplasticpolymer comprises a plurality of nano-imprints, wherein at least aportion of the plurality of nano-imprints are formed using a pair ofnano-imprint stamps, wherein the first of the pair of nano-imprintstamps faces the inner wall and the second of the pair of nano-imprintstamps faces the outer wall, wherein optionally at least a portion ofthe plurality of nano-imprints each have a re-entrant pore geometry,optionally formed using a process comprising a warm compression of thethermoplastic polymer, and optionally the re-entrant pore geometrycomprises an entrance diameter, or an average diameter if thenano-imprint is not circular, which is smaller than the maximum averagediameter within the nano-imprint, and optionally the warm compressioncomprises applying a warm compressive plastic deforming force in avertical direction to partially squash at least a portion of thethermoplastic polymer to the re-entrant pore geometry; and optionallythe re-entrant pore geometry comprises a nano-pore, wherein a ratio of amaximum inner-pore diameter to the entrance diameter is at least 1.05.24-30. (canceled)